LB0002 SAFETY &amp; EFFICACY OF SEL-212 IN PATIENTS WITH GOUT REFRACTORY TO COVENTIONAL TREATMENT: OUTCOMES FROM TWO RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, MULTICENTER PHASE III STUDIES
Authors: H. S. B. Baraf, A. Kivitz, S. Rhodes, S. Leung, O. Folarin, T. Gonzalez-Rivera, J. Sobierska, J. Christie, A. Patel, W. Dehaan, R. Azeem, P. Traber
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Despite availability of effective therapies for gout, a small proportion of patients suffer from refractory gout and/or are intolerant to standard therapies [1]. In these patients, the inability to maintain serum uric acid (sUA) levels &lt; 6 mg/dL may lead to severe clinical manifestations for which uricase-based therapies can be highly effective, though also immunogenic. SEL-212 is a once-monthly, novel 2-component, sequential uricase-based infusion therapy being investigated in patients with refractory gout. SEL-212 consists of an infusion of tolerogenic nanoparticles containing rapamycin (SEL-110) followed by pegadricase (SEL-037). The intent of this drug combination is to inhibit the formation of anti-uricase antibodies without the need for separate immunosuppressant therapies [2]. <h3>Objectives</h3> DISSOLVE I and II (D1 and D2, respectively) evaluated the safety and efficacy of SEL-212 in adults with refractory gout. <h3>Methods</h3> D1 (US Study, 12 months) and D2 (Global Study, 6 months), were placebo-controlled, double-blind, randomized clinical trials that evaluated two dose levels of SEL-110 (0.15 mg/kg [high-dose] or 0.1 mg/kg [low-dose]) prior to SEL-037 (0.2 mg/kg) infusion in adults (19-80 years). Participants with a history of symptomatic gout were enrolled if they had ≥ 3 gout flares within 18 months prior to screening or ≥ 1 tophus or a current diagnosis of gouty arthritis, failed to normalize sUA and control symptoms with any xanthine oxidase inhibitor, and were not previously exposed to a uricase-based therapy. Participants were randomized 1:1:1 between the two doses of SEL-212 and placebo administered intravenously every 28 days for 6 treatments. D1 participants were continued in a 6-month blinded extension phase under the initial treatment conditions (Fig. 1). The primary endpoint was defined as the percentage of participants who achieved and maintained sUA &lt; 6 mg/dL for ≥ 80% of the sixth 28-day treatment period (TP6) in the active treatment groups versus placebo (response rate). Safety and tolerability were assessed through monitoring of adverse events (AEs) and laboratory testing. <h3>Results</h3> A total of 265 participants (D1, n=112 (96% male, 66% ≥ 50 years); D2, n=153 (97% male, 72% ≥ 50 years) were randomized into the three treatment arms. Response rates in all treatment groups were significantly different from placebo (p ≤ 0.0015), with 56% and 47% of participants responding in the high-dose group and 48% and 41% in the low-dose group for D1 and D2, respectively (Table 1). The response rates in participants aged ≥ 50 years were 65% and 48% in the high-dose groups and 47% and 45% in the low-dose groups for D1 and D2, respectively (p ≤ 0.0044 vs placebo). Across all participants in the treatment groups, median sUA levels were reduced by ~96% and ~75% from baseline at TP6 for D1 and D2, respectively (p&lt;0.001 vs placebo). The safety profile of SEL-212 was favorable, with 3.4% and 4.5% of participants experiencing infusion reactions in the high and low-dose groups, respectively. Reports of gout flares were comparable between treatment groups and placebo. Six participants (3.4%) in the pooled active treatment groups experienced treatment-related serious AEs (n=4 anaphylaxis, n=2 gout flares). <h3>Conclusion</h3> In the DISSOLVE trials, once-monthly treatment with SEL-212 demonstrated statistically significant response rates and reductions in sUA versus placebo. The safety profile of SEL-212 was consistent with that of uricase therapies. Targeted immunomodulation with SEL-212 has the potential to provide a new uricase-based treatment option for patients with gout refractory to conventional therapies without the need for traditional immunosuppressants. <h3>References</h3> [1] Edwards NL. <i>Arthritis Rheum</i> 2008;58(9):2587-90. [2] Sands E, <i>et al. Nat Commun</i> 2022;13:272. <h3>Acknowledgments</h3> We would like to acknowledge all participants, investigators, and study personnel involved in the DISSOLVE phase III clinical studies. Writing support provided by Micheal Wilson, PhD, of Swedish Orphan Biovitrum. <h3>Disclosure of Interests</h3> Herbert S.B. Baraf Consultant of: Horizon Pharmaceuticals, Swedish Orphan Biovitrum, Selecta Biosciences, Speakers bureau: Horizon Pharmaceuticals, Grant/research support from: Horizon Pharmaceuticals, Swedish Orphan Biovitrum, Alan Kivitz Consultant of: AXDEV Group, Amgen, Pfizer, Janssen, Boehringer Ingelheim, AbbVie, Flexion, Gilead, Grünenthal, Orion, Regeneron, Sun Pharma Advance Research, and ECOR1, Speakers bureau: Merck &amp; Co, Eli Lilly, Novartis, Pfizer, Flexion, AbbVie, Amgen, Genentech, Regeneron, UCB, Horizon, and GSK, Shareholder of: Pfizer, GSK, Gilead, Novartis, and Amgen, Sheri Rhodes Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Sheldon Leung Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Olu Folarin Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Tania Gonzalez-Rivera Consultant of: Swedish Orphan Biovitrum, Employee of: Swedish Orphan Biovitrum, Joanna Sobierska Employee of: Swedish Orphan Biovitrum, Jacquie Christie Shareholder of: GSK Pharma, Employee of: Swedish Orphan Biovitrum, Anand Patel Speakers bureau: Lexicon Pharmaceuticals, Wesley DeHaan Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Rehan Azeem Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Peter Traber Consultant of: Selecta Biosciences, Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences.